Evolutionary adaptation to environmental and endogenous microbes has shaped the immunity and physiology of multicellular organisms. Convergent genetic studies of innate immunity in mammals and in Drosophila revealed a commonality in the ancient signaling pathways of host defense, motivating me to embark on the molecular genetic analysis of innate immunity in the simple host organism Caenorhabditis elegans. The long-term goal of this project is to understand the molecular mechanisms of host defense in C. elegans, with the anticipation that studies in this simple host organism will shed light on conserved mechanisms of innate immunity and the evolution and physiology of host-microbe interactions. During the last funding period, we have continued to establish the mechanisms of innate immunity in C. elegans, while also extending our work to encompass the integrative physiology of host responses to infection. We discovered a physiological role for the Unfolded Protein Response in innate immune tolerance and defined how polymorphisms in neuronal genes can modulate the behavioral avoidance of pathogenic bacteria, underscoring the role of the nervous system in responses to microbes. We also initiated a study to understand the molecular basis of immunosenescence in C. elegans, the age-associated decline in immune function. Our studies of the C. elegans host have emphasized the influence that microbial pathogens and innate immune activation can have on host physiology. In this renewal application, we bring together a number of insights gained from these studies and turn our attention to how host-microbe interactions influence the physiology of aging and innate immunity. The basic underlying hypothesis of our proposal is that microbial pathogens can influence longevity and immunity of the C. elegans host through the modulation of neuroendocrine signaling pathways. Our preliminary studies have established a requirement for the TGF-ss signaling pathway in the neuroendocrine regulation of host defense. In addition, we observe marked pathogen-induced changes in host neuronal gene expression that we have defined quantitatively using single-molecule fluorescent in situ hybridization methods. We have three aims. First, we will define how the TGF-ss pathway promotes host defense against pathogenic bacteria and assess the role of this pathway during immunosenescence. Second, we will define the host sensory mechanisms involved in responding to changes in the microbial environment and inducing changes in neuronal TGF-ss expression. Third, we will identify the microbial molecule(s) and corresponding genetic determinants that modulate host physiology through changes in TGF-ss-dependent neuroendocrine signals. We anticipate that these studies will illuminate how the microbial environment of the host can modulate diverse aspects of physiology, including processes contributing to aging and longevity.